PROJECT SUMMARY Epileptic seizure burden decreases health related quality of life, and is associated with increased morbidity and mortality. Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy. For about 60-70% of these patients, anti-epileptic medication is a successful treatment. In a subset of TLE patients gold standard clinical assessments identify the hippocampus as the seizure focus (mesial TLE or mTLE), and surgical resection of this region is a potential treatment for those that are drug refractory. However, even in these seemingly homogeneous patients with a well-defined seizure focus, seizure freedom rates from surgery range from approximately 58% to 80% of patients. Our recent work suggests that while the seizure focus may be the same across this group of patients, the network of seizure propagation may be variable. Using Magnetic Resonance Imaging (MRI) a presurgical functional and structural model network was characterized in those patients that were seizure free one year post surgery. Subsequent patients with networks that differed from this model had unsuccessful outcomes with no improvement or worsening of seizures within the first year after surgery. In patients with improvement from surgery whose presurgical propagation network was consistent with the model, variations in a few specific connections were associated with length of time until seizure recurrence (up to 3 years). This suggests a similar network is responsible for late seizure recurrence in these patients. Furthermore, by identifying this unique cohort of mTLE patients with similar network properties in whom late seizures may recur, we hypothesize that it is possible to quantify networks longitudinally as recurrence develops after surgery. Therefore, the overall goal of this project is to quantify presurgical and post-surgical MRI network connectivity and their relationship to seizure recurrence after mesial temporal lobe surgery. In Aim 1 the previously defined presurgical MRI functional and structural connectivity model of mTLE will be further developed and validated as a biomarker of long term seizure outcome. While the biomarker will include only presurgical connectivity measures, the development will be informed by the knowledge of how networks evolve after surgery as determined in Aims 2 and 3. In Aim 2 longitudinal post-surgical MRIs will be used to quantify functional and structural network evolution for three years after surgery and localize networks responsible for post-surgical seizures. Finally, Positron Emission Tomography (PET) will be used to localize the seizure focus via hypometabolism after seizure recurrence to compare with and to inform the networks identified in Aim 2. This work will ultimately result in the quantification of network evolution in seizure recurrence, and biomarkers of long term seizure outcome in mTLE.